Crosslinked polysaccharides, process for their preparation and their use

ABSTRACT

The invention relates to polysaccharides which are crosslinked with bifunctional crosslinkers and are no longer water-soluble but are still biodegradable, have a swelling of from 100 to 1000%, where the swelling, which means the percentage gain in weight, is determined by the following equation: ##EQU1## in which A is the percentage gain in weight, W o  is the weight of the dry polymer and W t  is the weight of the swollen polymer saturated with water. It likewise relates to a process for preparing the crosslinked polysaccharides and to the use of the crosslinked polysaccharides for coating and/or embedding medicinal active substances or drug compositions. The invention furthermore relates to a drug which contains an active substance which acts in the large intestine or an active substance which is broken down on passing through the stomach or small intestine, coated with or embedded in one of the crosslinked polysaccharides.

DESCRIPTION

The invention relates to polysaccharides cross-linked with bifunctionalcrosslinkers, to a process for their preparation, to their use forcoating and embedding drugs and to drugs coated and embedded using them.

The oral dosage form is a preferred administration of drugs. Drugs whichdo not act until the large intestine, eg. those employed for chronicinflammations of the large intestine or Crohn's disease, and drugs whichare normally broken down or digested under physiological conditions inthe stomach or in the small intestine or must be protected in order forthem to reach the large intestine unchanged. Examples of medicinalsubstances which are broken down or digested in the small intestineinclude peptide medicinal substances.

There is therefore a need for a film coating and an embedding materialby which, on oral administration, the administered active substance isprotected on transport through the body as far as the large intestineand is then released there. Peptide medicinal substances could thus beprotected, on oral use, from decomposition by gastric fluid as well asfrom decomposition by peptidases. Since the peptidase activity in thelarge intestine is only very low but the absorption of peptides takesplace in the large intestine, this would be an acceptable way toadminister peptide medicinal substances.

Owing to the natural physiological pH gradient between saliva andstomach on the one hand, and stomach and small intestine on the otherhand, it is now possible without special difficulties to develop drugforms which release their active substances specifically in the stomachor in the small intestine. This is achieved by embedding or coatingdrugs with ancillary substances which are soluble or resistant at theappropriate pH values.

Since, however, there is only little difference between the pH values onpassing from the small intestine into the large intestine, for targetingthe large intestine it is necessary to look for other utilizablephysiological differences which can be used to achieve small-intestineresistance and large-intestine degradability. The successful developmentof novel small-intestine resistant but large-intestine degradableancillary substances has not to date succeeded in opening uppossibilities to be implemented for targeting the large intestine.

DE 40 06 521 A1 (and European Patent Application 450 176 A1 whichcorresponds to it) describes sugar-containing polymers for coating andembedding medicinal substances. These sugar-containing polymers are usedto coat and/or embed pharmaceutical active substances which can beadministered orally and result in the active substances which arecontained in the polymers not being released until the large intestine.The polymers described in this publication have the disadvantage thatthey need complicated preparations and are crosslinked withpolyisocyanates.

Numerous review articles recently have referred to the possibilities ofabsorption in the large intestine (M. L. G. Gardner (1988):Gastrointestinal absorption of intact proteins, Ann. Rev. Nutr. 8,329-350; P. Gruber, M. A. Longer and J. R. Robinson (1987): SomeBiological issues in oral controlled drug delivery, Adv. Drug Deliv.Rev. 1, 1-18; T. T. Karrarly (1989): Gastrointestinal absorption ofdrugs, Crit. Rev. 6 (1), 39-86).

Studies on administrations of medicinal substances into the largeintestine have also been published and refer to the suitability of thisregion not only as target organ for topically active medicinalsubstances but also absolutely as absorption site. Thus, P. R. Bieck(1987, Arzneistoffresorptionen aus dem menschlichen Dickdarm--neueErkermtnisse, Acta Pharm. Technol. 33 (3), 109-114) describes howseveral medicinal substances introduced into the large intestine viatubes or by means of controlled release HF capsules, including theβ-receptor blockers oxprenolol and metoprolol as well as isosorbide5-mononitrate, are absorbed virtually just as well as from the smallintestine.

The present invention is based on the object of providing crosslinkedpolysaccharides, process for their preparation, their use and drugs,with which protected transport of medicinal substances through thestomach and small intestine is possible with subsequent targeted releaseof the medicinal substance in the large intestine. The intentionaccording to the invention is to make possible local administration ofmedicinal substances in the large intestine, eg. in the case of chronicinflammations of the large intestine or Crohn's disease, and of activesubstances which are normally broken down or digested under thephysiological conditions in the stomach or small intestine. Theintention of the present invention is to open up the development ofnovel small-intestine resistant but large-intestine degradable ancillarysubstances for targeting the large intestine.

The Applicant has found that the small microbial colonization of thedistal sections of the small intestine compared with the well-developedmicroflora in the cecum is particularly suitable for developingsubstances which make it possible to achieve the stated object.

The Applicant has found that certain crosslinked polysaccharides aresuitable, by reason of their enzymatic degradability by the microfloraof the large intestine, for use as film formers for developing noveldrug forms which are soluble in the large intestine. Because of theenzymatic degradability by the bacterial cultures in the largeintestine, the medicinal substances are specifically released there.

The invention relates to polysaccharides which are crosslinked withbifunctional crosslinkers and are no longer water-soluble but are stillbiodegradable, have a swelling of from 100 to 1000%, where the swelling,which means the percentage gain in weight, is determined by thefollowing equation: ##EQU2## in which A is the percentage gain inweight, W_(o) is the weight of the dry polymer and W_(t) is the weightof the swollen polymer saturated with water.

The invention furthermore relates to a process for preparing thecrosslinked polysaccharides, according to which a polysaccharide with amolecular weight of from 100,000 to 10 million, specifically

Galactomannans: 100,000-1 million, preferably 500,000-1 million

Laminarin: 100,000-1 million, preferably 500,000-1 million

Glucomannan: 100,000-1 million, preferably 500,000-1 million

Dextran: 100,000-10 million, preferably 1 million-10 million

Pectins: 100,000 -500,000

Arabinogalactan: 100,000-300,000

Xylan: 100,000-500,000,

is suspended in an aliphatic diglycidyl ether, a C₄ -C₁₀ -aliphaticdicarboxylic acid or its reactive derivative or a C₄ -C₁₀ -aliphaticdialdehyde with or without the addition of an inert organic solvent orswelling agent, the suspension is heated to a temperature in the rangefrom room temperature to 80° C., a catalytic amount of a base is addedto the suspension, the reaction mixture is stirred at the statedtemperature for a period of from 1 to 15 hours, and subsequently thecrosslinked polysaccharide is separated off in a manner known per se andwashed where appropriate one or more times with water, methanol oracetone.

The invention likewise relates to the use of the crosslinkedpolysaccharides for coating and/or embedding medicinal active substancesor drug compositions and to a drug which contains an active substancewhich acts in the large intestine or an active substance which is brokendown on passing through the stomach or small intestine, coated with orembedded in one of the crosslinked polysaccharides.

The Applicant has surprisingly found that crosslinked polysaccharideswhich, in the uncrosslinked state, are broken down by the glycosidasesof the large intestine microflora and which have been crosslinked withbifunctional crosslinkers in such a way that they are just no longersoluble in water but still biodegradable comply with the statedrequirements. If derivatization is too extensive the degradability islost. Accordingly, the polysaccharide may be modified according to theinvention only just enough to suppress the solubility in water. This isdone by crosslinking the polysaccharides with suitable crosslinkers. Itmust be noted in this connection that short crosslinking times and theuse of long-chain crosslinkers result in correspondingly loose networksinto which the enzyme can penetrate and break down the filmenzymatically.

Polysaccharides which can be used according to the invention as startingpoints for the crosslinkings are listed in the following table.

    ______________________________________                                        Table of polysaccharides used according to the invention                      Poly-                 Degrada-                                                saccharide                                                                           Building block bility   Mode of degradation                            ______________________________________                                        Galacto-                                                                             (1,4)-β-mannose                                                                         +++      Endoenzyme                                     mannan (1,6)-α-galactose Degradation products:                                                         Oligosaccharides                               Laminarin                                                                            (1,3)-β-glucose                                                                         +++      Exoenzyme                                                                     Degradation products:                                                         Oligosaccharides                               Pectins                                                                              (1,4)-α-galacturonic acid                                                              +++      Exoenzyme                                             (partial methyl ester)  Degradation products;                                                         Mono-, disaccharides                           Gluco- (1,4)-β-mannose                                                                         +++      Endoenzyme                                     mannan (1,4)-β-glucose    Degradation products:                                                         Oligosaccharides                               Arabino-                                                                             arabinose      +++                                                     galactan                                                                             galactose                                                              Xylan  (1,4)-β-xylopyranose                                                                    ++       Exoenzyme                                                                     Degradation products:                                                         Mono-, disaccharides                           Dextran                                                                              branched glucans:                                                                            +++      Exoenzyme/                                            α-1,6-D-glucose,  Endoenzyme                                            α-1,3-glucose (branched)                                         ______________________________________                                    

The preferred polysaccharides among those listed in the table aregalactomannan, glucomannan and dextran. Galactomannan is particularlypreferred. The polysaccharides used according to the invention have amolecular weight of from 100,000 to 10 million. The molecular weight isnot particularly critical as long as the abovementioned conditions aremet, that is to say the polysaccharides are, in the uncrosslinked state,broken down by the glycosidase of the large intestine microflora and areno longer soluble in water after crosslinking. The preferred andparticularly preferred molecular weights for some of the polysaccharidesare indicated below.

Galactomannans: 100,000-1 million, preferably 500,000-1 million

Laminarin: 100,000-1 million, preferably 500,000-1 million

Glucomannan: 100,000-1 million, preferably 500,000-1 million

Dextran: 100,000-10 million, preferably 1 million-10 million

Pectins: 100,000-500,000

Arabinogalactan: 100,000-300,000

Xylan: 100,000-500,000

Suitable polysaccharides are broken down by enzymes. The endoenzyme(1,4)-β-mannase is demonstrably produced by the flora of the human largeintestine.

Furthermore there are copious numbers of the bacterial genus Bacteroidespresent in the human large intestine, which genus produces anexo/endoenzyme system which breaks down α-1,6-glycosidic linkages whichare present, for example, in dextran. This explains why the largeintestine microflora is able to cleave not only β-1,4- but alsoα-1,6-glycosidic linkages. The polysaccharides used according to theinvention are not attacked by amylases and are thus stable in the smallintestine.

The crosslinked polysaccharides which are preferably used are thosecleaved by endoenzymes. The endoenzymes cleave the polysaccharides inthe interior and relatively rapidly, leading to immediate release of theactive substance. The cleavage takes place slower with exoenzymes whichattack the end of the polysaccharides.

The said polysaccharides are not suitable in the uncrosslinked formasfilm coating or embedding material because they are water-soluble andare dissolved and broken down too rapidly. They are thereforecrosslinked according to the invention.

Various reagents can be used as crosslinkers according to the invention.The crosslinkers which are preferably used are those already employedand regarded as acceptable in pharmacology. The crosslinkers must bebifunctional, and examples are: aliphatic diglycidyl ethers such as1,4-butanediol diglycidyl ether or 1,6-hexanediol diglycidyl ether, C₁-C₄ -aliphatic dicarboxylic acids such as succinic acid, glutaric acid,adipic acid or their reactive derivatives such as the acid dichloridesor anhydrides, C₄ -C₁₀ -aliphatic dialdehydes such as, for example,glutaraldehyde, succinaldehyde or adipaldehyde. Of these, 1,4-butanedioldiglycidyl ether, 1,6-hexanediol diglycidyl ether, adipic acid, adipoylchloride and adipaldehyde are preferred. The crosslinkers react with theOH groups of the polysaccharides, and the crosslinked product obtainedin this way is insoluble in water but swellable and dispersible in waterand forms qualitatively good films.

The water uptake by the crosslinked polysaccharide, ie. the swelling ofthe crosslinked polysaccharide, is used for characterization. Thecrosslinked polysaccharides according to the invention have a swellingof from 100 to 1000%, preferably from 150 to 850%. The swelling isdetermined by weighing 100 mg of the crosslinked polysaccharides in theform of the polymer films into an ampoule and adding 10 ml of water.After 1, 5, 8, 20, 48 and 73 hours the film is removed from the waterand dabbed on cellulose and weighed. The weight gain can be calculatedby the following formula: ##EQU3## in which A is the percentage gain inweight, W_(o) is the weight of the dry polymer and W_(t) is the weightof the swollen polymer. In the present application the swelling isunderstood to be the value obtained when W_(t) is constant.

The swelling depends slightly on the crosslinker. As indicated above, itis generally in the range from 100 to 1000%. When the diepoxides areused it is from 100% to 800%, preferably 200 to 400%. If dicarboxylicacids, their reactive derivatives and dialdehydes are used, the swellingis from 150 to 850%, preferably from 200 to 550%. The skilled person iseasily able to establish by suitable preliminary tests what ratios ofamounts of uncrosslinked polysaccharide and crosslinker must be used andwhether the resulting crosslinked polymer has the properties accordingto the invention. The following examples indicate the ratios forcrosslinking with diepoxides and with dicarboxylic acids or dialdehydes.

Crosslinkings with Diepoxides

In order to obtain the required crosslinked products for example oncrosslinking of galactomannan with 1,4-butanediol diglycidyl ether and1,6-hexanediol diglycidyl ether (diepoxides), the following ratios ofthe amounts of substances must be complied with. The ratios of theamounts of substances are based on the primary and secondary OH groupsof the sugar building blocks. The products resulting from thecrosslinking can be characterized on the basis of their swelling andstability in water and on the basis of their degradability byhemicellulases. Polysaccharides with insufficient crosslinking showexcessive swelling or the films disintegrate. Polysaccharides withexcessive crosslinking cannot any longer be broken down by theappropriate enzymes.

    ______________________________________                                                           Crossl.      Film- Stabil.                                                                             Degrada-                          Po  DiEp   NaOH    time  Swelling                                                                             form  in H.sub.2 O                                                                        bility                            ______________________________________                                        1   3      0.001   140 min                                                                             800%   yes   low   yes                               1   3      0.02    150 min                                                                             550%   yes   +     yes                               1   4      0.03    170 min                                                                             300%   yes   good  yes                               1   5      0.04    180 min                                                                             250%   yes   very  yes                                                                     good                                    1   5      0.06    300 min                                                                             150%   mod-  --    yes                                                               erate                                         1   5      0.1     300 min                                                                             <100%  no    --    no                                ______________________________________                                         Notes: Po = polysaccharide, DiEp = diepoxide, the indicated ratios are        ratios of amounts of substances.                                         

All crosslinked products with a swelling of from 100% to 800%,preferably 200 to 400%, are broken down by hemicellulases. Thesecrosslinked products are preferred when C₄ -C₁₀ -alkanediol diglycidylethers are used.

Crosslinkings with Dicarboxylic Acids and Dialdehydes

The following ratios of amounts of substances must be complied with incrosslinking with dicarboxylic acids, their reactive derivatives anddialdehydes. The ratios of amounts of substances are based on theprimary and secondary OH groups in the sugar building blocks. Theresulting products can be characterized by the swelling in water, thefilm-forming properties, the stability in water and the degradabilitywith hemicellulases. Polysaccharides with excessive crosslinking cannotany longer be broken down.

    ______________________________________                                            DiCb/                 Crossl.      Film-                                                                              Degrada-                          Po  DiCbcl  DCC    4-DMAP time  Swelling                                                                             form bility                            ______________________________________                                        1   3.8     1.3    --     24 h  850%   yes  yes                               1   9.5     9.5    --     24 h  730%   yes  yes                               1   39.7    12     --     24 h  630%   yes  yes                               1   5.6     6      --     48 h  --     no   yes                               1   0.48           1.2    12 h  534%   yes  yes                               1   1              2      12 h  360%   yes  yes                               1   2              4      20 h  300%   yes  yes                               1   4              8      30 h  160%   no   yes                               ______________________________________                                         Notes: Po = polysaccharide, DiCb = dicarboxylic acid, DiCbcl = dicarbonyl     chloride, 4DMAP = 4dimethylaminopyridine, DCC = dicyclohexylcarbodiimide.

The most important feature for characterization is the swelling of thecrosslinked products and the enzymatic degradability. A strong esterband is evident at 1740 in the IR of polysaccharides crosslinked withdicarboxylic acids.

The films obtained from the crosslinked polysaccharides are insoluble inwater but have various degrees of swelling in water which depend on thedegree of crosslinking.

All these films are degradable both in the Freiburger large intestinemicroflora test, which is described hereinafter, and with pureβ-mannanase or other exo/endoenzyme systems which occur in the largeintestine. Release tests with films which swell only slightly and whichwere prepared from galactomannan as polysaccharide and 1,4-butanedioldiglycidyl ether as crosslinker were able to show that release of a dyesubstance took place only after addition of the enzyme β-mannanase.

Crosslinked polyacrylates have already been used for this purpose by M.Saffran et al. (M. Saffran, G. S. Kumar, C. Savriar, J. C. Burnham, F.Williams and D. C. Neckers (1986): A new approach to the oraladministration of Insulin and other peptide drugs, Science 233,1081-1084). However, these did not show the desired effect. It wastherefore surprising that the crosslinked polysaccharides made availableaccording to the invention were usable for the said purpose. Thecrosslinked polysaccharides prepared by M. Saffran et al. were evidentlycrosslinked too much and insufficiently swellable so that they werebroken down too slowly by the reductases in the large intestinemicroflora.

The invention likewise relates to a process for preparing the novelcrosslinked polysaccharides as indicated above.

In the process according to the invention, the polysaccharide with themolecular weight indicated above is suspended in the crosslinker asindicated, with or without the addition of an inert solvent or swellingagent such an aliphatic alcohol. The absence of a solvent is preferred.The resulting suspension is heated while stirring to a temperature inthe range from room temperature to 80° C., preferably to 60° C. Thechosen temperature must not be so high that the polysaccharide formsaggregates. A catalytic amount of a base is added to the suspension. Thenature of the base is not particularly important and, in general, alkalimetal hydroxides such as sodium hydroxide or potassium hydroxide, alkalimetal carbonates or organic bases such as, for example,4-dimethylaminopyridine are used. However, it is also possible to useother bases. The reaction mixture is then stirred at room temperature orat a temperature of up to 80° C., preferably up to 60° C., particularlypreferably up to 40° C., for a time of from 1 to 15 hours, preferably 1to 6 hours. Subsequently, the crosslinked polysaccharide is removed in amanner known per se, for example by centrifugation, filtration etc. Forpurification, it is washed one or more times with water in a mannerknown per se. The product is dried and can then be used directly.

The novel crosslinked polysaccharides according to the invention can beused for coating or embedding medicinal active substances or drugcompositions which are to be specifically used locally in the largeintestine, or for protecting active substances which are normally brokendown or digested under physiological conditions in the small intestineor in the stomach, or else for producing sheets which contain thesemedicinal active substances or drug compositions. In such cases it washitherto necessary as a rule to administer the corresponding medicinalactive substances parenterally.

It was surprising that the polysaccharides crosslinked according to theinvention can be synthesized in one synthetic step, withstand thegastrointestinal tract undamaged and can be rapidly broken down in thelarge intestine.

The invention thus furthermore relates to the use of the crosslinkedpolysaccharides according to the invention for producing film coatingsand embeddings of pharmaceutical active substances which can beadministered orally and for which release of active substance isintended to take place in the large intestine. The medicinal activesubstances or drug compositions are coated with the crosslinkedpolysaccharides according to the invention and/or embedded in them. Thecoating or embedding takes place by processes known per se, described,for example, for coatings, in Bauer, Lehmann, Osterwald, Rothgang:Uberzogene Arzneiformen, Wiss. Verlagsges. Stuttgart, 1988, and forembeddings in Bauer, Fromming, Fuhrer: Pharmazeut. Technologie, 3rdedition, G. Thieme Verlag Stuttgart, 1991, pages 278,353 and 358.

It is possible, for example, to produce granules, pellets, tablets etc.in a manner known per se.

Suitable examples of active substances which can preferably beformulated with the crosslinked polysaccharides according to theinvention are those medicinal active substances which are broken down ordigested in the stomach or small intestine and therefore could not inthe past be administered orally, and drugs intended not to act until thelarge intestine, such as drugs acting on disorders of the largeintestine, and peptide drugs. Examples are: peptides, cardiovasculartherapeutic agents, antirheumatics/analgesics, compositions for thetherapy of disorders of the large intestine such Crohn's disease andulcerative colitis, antiasthmatics, antifibrinolytics, antihemorrhagics,antitumor agents, enzyme products, antibiotics, antimycotics, substancesacting on the central nervous system.

Examples of peptide active substances are: ACTH (adrenocorticotropichormone), corticostatin, calcitonin, insulin, oxytocin, somatostatin andanalogs, LHRH analogs, bombesin analogs, cholecystokinin andderivatives, endothelin and analogs, thrombin inhibitors, peptide growthfactors (eg. IGF, EGF, NGF), magainins (PGS peptides), gastrin analogs,bradykinin analogs, parathormone analogs, neurokinin and analogs, VIPand analogs, ANP (atrial natriuretic peptide) and analogs, neokyotrophinand analogs, angiotensin analogs, enkephalins, dynorphins, dermorphins,deltorphins, renin-inhibiting peptides, tumor growth factor peptides,MSH (melanocyte stimulating hormone) analogs, mitotoxins, tyrphostins,chromogranin A, thymopentin, TRH and analogs, substance P, tuftsin,fibronectin, and peptide immunomodulators such as cyclosporin A, FK 506,neuropeptide Y and NPK.

Preferably used according to the invention are peptides preparedbiotechnologically, in particular lower peptides.

The microflora test of A. Sarlikiotis (A. Sarlikiotis, J. Betzing, Ch.Wohlschlegel and K. H. Bauer (1992): A new in-vitro method for testingcolon targeting drug delivery systems or excipients, in the press:Pharmaceutical and Pharmacological Letters, Springer VerlagInternational) was used to test crosslinked polysaccharides degradablein the large intestine and the resulting drugs.

The following examples illustrate the invention:

EXAMPLE 1

Crosslinking of galactomannan with 1,4-butanediol diglycidyl ether

2.0 g of spray-dried galactomannan are suspended in 26.7 g of1,4-butanediol diglycidyl ether in an Erlenmeyer flask which can beclosed. This suspension is heated to 50° C. After this temperature isreached (10 min), 3.5 ml of 0.2N NaOH are cautiously added dropwise.During this no or only slight aggregate formation should occur. Thisreaction mixture is left to stir at 50° C. until the end of the reactionperiod. After the reaction is complete, the suspension is centrifuged toremove the polymer. The crosslinked polysaccharide removed bycentrifugation is subsequently washed several times with water. Forfurther purification, the polymer is washed with acetone, lengthystirring in acetone being beneficial. The crosslinked galactomannanobtained in this way can be dispersed in water with the aid of anUltraturrax. Qualitatively good films can be produced from such aqueousdispersions. The minimum film-forming temperature is about 50° C., andthe degree of swelling is from 400 to 600%.

EXAMPLE 2

Crosslinklng of galactomannan with 1,6-hexanediol diglycidyl ether

2.0 g of spray-dried galactomannan are suspended in 26.7 g of1,6-hexanediol diglycidyl ether in an Erlenmeyer flask which can beclosed. This suspension is heated to 50° C. After this temperature isreached (10 min), 3.5 ml of 0.2N NaOH are cautiously added dropwise.During this no or only slight aggregate formation should occur. Thisreaction mixture is left to stir at 50° C. until the end of the reactionperiod. After the reaction is complete, the suspension is centrifuged toremove the polymer. The crosslinked polysaccharide removed bycentrifugation is subsequently washed several times with water. Forfurther purification, the polymer is washed with acetone, lengthystirring in acetone being beneficial. The crosslinked galactomannanobtained in this way can be dispersed in water with the aid of anUltraturrax. Qualitatively good films can be produced from such aqueousdispersions. The minimum film-forming temperature is about 50° C., andthe degree of swelling is from 400 to 600%.

EXAMPLE 3

Crosslinking with adipic acid

(a) 2.0 g of spray-dried galactomannan are suspended in 20.0 ml ofabsolute chloroform in a round-bottom flask. 29.0 g of adipic acid,which is less than the stoichiometric amount, and 41.0 g ofdicyclohexylcarbodiimide as water-binding reagent are added to thissuspension. This dispersion is refluxed at 60° C. for 48 hours. Thesuspension is subsequently filtered with suction and treated with about500 ml of hot methanol in the Soxhlet process for 24 hours to remove theurea derivative which is formed. The polysaccharide product obtained inthis way is insoluble in water but degradable with enzyme solution. Thedegree of swelling is about 400 to 600%.

(b) 2.0 g of spray-dried galactomannan are suspended in 20 ml ofdimethylformamide in a round-bottom flask. 6.1 g of adipoyl chloride areadded to this suspension. Subsequently 8.1 g of 4-dimethylaminopyridine,which is the amount equivalent to the acid chloride, are added. Thereaction mixture is subsequently heated to 60° C. The mixture is left atthis temperature for about 15 hours. The product obtained in this way isfiltered off with suction and purified with about 500 ml of hot methanolin the Soxhlet process for several hours. The degree of swelling is 400to 600%.

EXAMPLE 4

Crosslinking with Succinaldehyde

2.0 g of spray-dried galactomannan are suspended in 14.19 g ofsuccinaldehyde in a round-bottom flask. An appropriate amount ofdicyclohexylcarbodiimide is added as water-binding agent to thissuspension, and furthermore 3.0 g of ammonium nitrate as catalyst. It isalso possible to use anhydrous mineral acids such as sulfuric acid orelse 2,4-dinitrobenzoic acid as catalyst. This reaction mixture isstirred tightly closed at 50° C. for about 15 hours. The productobtained in this way is filtered off with suction and treated with about500 ml of hot methanol with the aid of a Soxhlet for 24 hours. Theproduct purified in this way is dried in an oven at 50° C. The degree ofswelling is 300 to 500%.

We claim:
 1. A pharmaceutical composition which comprises an activesubstance which acts in the large intestine or an active substance whichis broken down on passing through the stomach or small intestine, coatedwith or embedded in a polysaccharide selected from the group consistingof galactomannans, laminarin, pectins, arabinogalactans, xylans andglucomannans which is crosslinked with bifunctional crosslinkers and isno longer water soluble but is still biodegradable, has a swelling offrom 100 to 1000%, where the swelling, which means the percentage gainin weight, is determined by the following equation: ##EQU4## in which Ais the percentage gain in weight, W_(o) is the weight of the dry polymerand W_(t) is the weight of the swollen polymer saturated with water. 2.A composition as defined in claim 1, which comprises as active substancea peptide drug.
 3. A composition as defined in claim 2, which is in theform of tablets, granules or capsules.
 4. A method of coating and/orembedding medically active substances or drug compositions whichcomprises the step of coating or embedding said substances orcompositions with a crosslinked polysaccharide as defined in claim
 1. 5.A pharmaceutical composition which comprises an active substance whichacts in the large intestine or an active substance which is broken downon passing through the stomach or small intestine, coated with orembedded in a crosslinked polysaccharide wherein the crosslinker is amember selected from the group consisting of aliphatic diglycidylethers, C₄ -C₁₀ -aliphatic dicarboxylic acids or their reactivederivatives or C₄ -C₁₀ -aliphatic dialdehydes.
 6. A pharmaceuticalcomposition which comprises an active substance which acts in the largeintestine or an active substance which is broken down on passing throughthe stomach or small intestines, coated with or embedded in acrosslinked polysaccharide wherein the crosslinker is a member selectedfrom the group consisting of 1,4-butanediol diglycidyl ether,1,6-hexanediol diglycidyl ether, succinic acid, glutaric acid, adipicacid or their reactive derivatives, succinaldehyde, glutaraldehyde oradipaldehyde.